Although age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, the techniques for diagnosing and treating eye disease are decidedly lacking. The main indicator used to diagnose pre-symptomatic AMD is the presence of drusen as viewed using fundus photography. Drusen are heterogeneous deposits of oxidized lipids and proteins that form in or on the sub-retinal extracellular matrix sheet termed Bruch's membrane (BrM). BrM is located between the highly metabolic photoreceptors of the outer retina and its main vascular supply, the choriocapillaris, which delivers approximately 90% of the metabolites required by photoreceptors via diffusion. However, when drusen are present in BrM, the distance these metabolites must travel can drastically increase, resulting in a flattening of the concentration gradient and reduction in metabolite delivery. Though small or sparse drusen are recognized as a normal part of aging and not associated with disease progression, large and/or numerous drusen can be considered signs of early AMD. Other hallmarks of AMD include thickening of BrM, decreased BrM hydrolytic conductivity, and vascular dropout, all of which may further contribute to AMD pathology due to inadequate metabolite delivery.
Because oxygen is well-known to be the limiting metabolite in the outer retina, several groups have proposed oxygen deficiency as a key player in multiple degenerative retinal diseases including AMD. Photoreceptors of the outer retina consume oxygen via aerobic respiration to efficiently produce the energy required to maintain dark current for phototransduction. The theory of hypoxia-induced retinal degeneration underlying vision loss is supported by a growing amount of in vitro, in vivo, ex vivo, and clinical evidence.
Numerous studies have demonstrated the importance of oxygen regulation in maintaining retinal cell homeostasis as both hypoxia and hyperoxia are capable of inducing apoptosis. In vivo studies using a variety of animals including rats, cats, and non-human primates have shown that oxygen concentration approaches zero near the layer of photoreceptor inner segments even under healthy conditions. Because oxygen concentration at the inner segment is so tightly-regulated, disease-related morphological changes that are frequently as large as 30% of the retina's total thickness may disrupt this balance of supply and consumption. These changes may be especially critical in the macula, an area where a thinner and more porous BrM has evolved to combat the lack of retinal vasculature and high density of the more metabolically-costly cone photoreceptors.
Clinically, oxygen supplementation has been shown to decrease photoreceptor death in patients with retinal detachment. This therapy aims to counteract the drop in oxygen delivery associated with a pathological increase in diffusion distance by raising the peak dissolved oxygen concentration. Others have shown that photoreceptor degeneration is (approximately 16-fold) more highly correlated with drusen height than with drusen width. This evidence is again congruent with the idea that photoreceptor degeneration may be a result of insufficient metabolite transport due to increased diffusion distance while simultaneously calling into question the validity of using drusen width as the main criteria for AMD diagnosis. In addition, wet AMD (choroidal neovascularization) is likely the body's attempted healing response to outer retinal hypoxia. When challenged with insufficient oxygen, cells of the retina attempt to increase vascular density and perfusion through a vascular endothelial growth factor (VEGF) dependent pathway. However, excessive VEGF signaling in the eye can cause aberrant vessel growth into the neural retina resulting in edema and rapid visual loss as seen in wet AMD.